I am an Assistant Professor in the Division of Pediatric Critical Care at Vanderbilt University School of Medicine. As a Pediatric Intensivist, I encounter patients on a regular basis that suffer from disease-related inflammation, which despite advances in the medical field, still lead to significant morbidity and mortality. I have always had a strong interest in immunity, inflammation and vascular biology. My previous work examined platelet-dependent mechanisms of lipopolysaccharide (LPS)-induced thrombosis. During that time, I focused on toll-like receptor 4 (TLR4)-dependent mechanisms of microvascular thrombosis using intravital microscopy and platelet aggregometry in animal models of endotoxemia. This award will allow me to continue to explore mechanisms of inflammation, specifically the modulation of endothelial injury during infections. Equally important, the activities pursued during this award will enhance my career development as a physician-scientist through a structured curriculum and mentored oversight to help me achieve successful research independence. Hospital-acquired infections are a leading cause of morbidity and mortality in critically-ill patients, among which critically-injured burn patients ar particularly vulnerable. Severe infections cause significant endothelial dysfunction and injury that is a consequence of alterations within nitric oxide and reactive oxygen species generation. However, it is unclear how infections specifically modulate these pathways in endothelial cells. Furthermore, there are no current preventative strategies available to modulate endothelial injury during infection. In this proposal, we will focus on endothelial nitric oxide synthase (eNOS)- dependent changes in endothelial function during infection and apply a TLR4-directed modulator, monophosphoryl lipid a (MPLA).
Aim 1 : Establish the mechanism by which endothelial TLR4 signaling alters eNOS function. The focus of these experiments will be to define the mechanisms by which eNOS dysfunction and associated alterations in nitric oxide and reactive oxygen species generation are induced by TLR4 activation.
Aim 2 : Determine the mechanism of MPLA-induced inflammatory modulation in endothelial cells. We will determine the mechanisms by which MPLA treatment prior to microbial challenge induces a protective effect on human endothelial cells.
Aim 3 : Define the ability of MPLA to prevent endothelial dysfunction in the setting of a burn-wound infection. In these studies, we will examine how MPLA prevents systemic endothelial- dependent vascular dysfunction in a clinically relevant animal model of burn-wound infection. The goal of this study is to understand the intracellular mechanisms leading to endothelial dysfunction and define the role of eNOS-dependent signals induced by infection. If the negative effects on the endothelium can be modulated with MPLA, this finding will have immediate therapeutic potential. The inflammatory response of burn injury with acquired infection is unique because these vulnerable patients typically come to medical attention before the infection becomes significant. It is therefore highly amenable to preventative therapy.
Hospital-acquired infections are a leading cause of morbidity and mortality in critically-ill patients. The purpose of this study is to focus on the effects of infections on endothelial cells, which occupy the interface between the host's immune system and the infected tissue. We will examine endothelial-specific mechanisms of nitric oxide synthase dysfunction relating to infection and examine the role of receptor-directed modulators to prevent the detrimental inflammatory effects acquired infections have on the endothelium.
|Stark, Ryan J; Koch, Stephen R; Choi, Hyehun et al. (2018) Endothelial nitric oxide synthase modulates Toll-like receptor 4-mediated IL-6 production and permeability via nitric oxide-independent signaling. FASEB J 32:945-956|
|Koch, Stephen R; Lamb, Fred S; Hellman, Judith et al. (2017) Potentiation and tolerance of toll-like receptor priming in human endothelial cells. Transl Res 180:53-67.e4|
|Luan, Liming; Patil, Naeem K; Guo, Yin et al. (2017) Comparative Transcriptome Profiles of Human Blood in Response to the Toll-like Receptor 4 Ligands Lipopolysaccharide and Monophosphoryl Lipid A. Sci Rep 7:40050|
|Stark, Ryan J; Choi, Hyehun; Koch, Stephen R et al. (2016) Endothelial cell tolerance to lipopolysaccharide challenge is induced by monophosphoryl lipid A. Clin Sci (Lond) 130:451-61|